Characteristics of Desenitization of Insulin Secretion. Prolonged hyperglycemia is presumed to cause impaired insulin secretion in human diabetes (both NIDDM and IDDM) resulting in exacerbated impairment of glucose homeostasis. Recently, using a novel computer-programmable perifusion/perfusion apparatus, we have demonstated that desensitization to glucose and other secretagogues can be demonstrated with fully in vitro isolated islet, and whole pancreas preparations. It is proposed: I) To evaluate further the characteristics of glucose desensitization in well-defined systems; and II) to examine the holistic effect of peptide extracts from plasma of NIDDM and related subjects on islet stimulation desensitization. I. Particular emphasis will be placed on: 1) the effectiveness of other secretagogues to release insulin during glucose-induced desensitization, and the ability of these secretagogues to either desensitize, or prevent, desensitization; 2) the interrelationships between stimulated secretion, desensitivity, and time-dependent potentiation; 3) the effects of oscillatory patterns of secretagogues on the kinetics of desensitization; 4) the changes in synthesis (measured both as 3H-leucine incorporation and total insulin production); 5) the processing of proinsulin to insulin; 6) and possible mechanisms of desensitization as reflected by changes in 45 Ca influx/efflux and c-AMP levels. II. Hydrophobic polypeptides (including most endocrine peptides) will be isolated by C18 SepPak adsorption from the plasmas of subjects with various forms or degrees of NIDDM and insulin resistance. The effect of these extracts on islet stimulation - desensitization will be tested at the original peptide ratios and plasma concentrations.